Immune-mediated diseases arise when errors occur within the immune system. Normally the immune response carries the potential to destroy foreign antigens whilst at the same time protecting against auto-immune attack. This exquisite ability to discriminate between “self” and “non-self” is orchestrated by the T lymphocytes: these cells ensure destructive aggressive activity only kills foreign targets whilst the immune response to the host (“self”) is actively protective and tolerant.
Dominant antigen-specific tolerant T lymphocytes include T regulatory cells (Treg), that perform an important role in moderating the immune response in an organism so as to maintain self-tolerance. Cells conforming to the Treg phenotype are a specialized group of T lymphocytes that express cell surface'markers including CD4, CD25, CTLA-4, and GITR. Treg cells express the transcription factor Foxp3. Foxp3 functions as a transcriptional repressor required for lymphocyte development down the Treg lineage and loss of Foxp3 function typically results in early death in humans due to the over-whelming auto-immune disease known as IPEX (immunodysregulation polyendocrinopathy enteropathy X-linked syndrome). Treg cells are predominantly derived from the thymus, where they develop under a rigorous process of selection to ensure their self-tolerant reactivity prior to release into wider circulation. Circulating Treg cells contribute to down-regulation of the body's aggressive immune responses against foreign pathogens. Treg cells also dominate and suppress any aggressive immune responses that may otherwise lead to attack of the body's own tissues (i.e. self tolerance).
Disease can ensue when self-tolerant Treg cells become weakened, thereby allowing aggressive cells to break through. In some individuals crippling auto-immune diseases will develop. Such inappropriate immune activity is thought to underly a wide number of diseases that lack curative therapy including rheumatoid arthritis, type I diabetes mellitus, systemic lupus erythematosis (SLE), psoriasis, and Crohn's disease to name a few.
Immune tolerance is also of crucial importance in the field of organ transplantation. There is a critical shortage of donor organs and it is of primary concern that appropriate tissue typing is conducted on the donor tissue and the recipient prior to transplantation. In spite of an apparently good match between a recipient host and a donor, the recipient's immune system will naturally recognize the allografted tissue as ‘foreign’ and if left uncontrolled will reject the transplant. Consequently, donor organ recipients must remain on immunosuppressive therapy for the remainder of their lives following transplant. Even then, recipients are subject to progressive chronic rejection within the blood vessels of the transplanted organ due to an insidious process that is not controlled by current immunosuppressive drugs: such chronic vascular rejection eventually blocks the blood flow within the transplanted organ causing organ failure. Without a new organ transplant—unlikely given the shortage of organs—or dialysis in the case of kidney graft recipients, the patient will die.
In 2004 around 15,000 kidney transplant procedures were carried out in the US alone, with a one year graft survival rate of around 90% (from OPTN/SRTR Data as of May 1, 2006). Nevertheless, at the filing date of this application over 70,000 people were on the waiting list for a kidney transplant in the US, clearly demonstrating that demand outstrips supply many times over. For other organs the graft survival rate falls, for example the one year survival rate for liver transplants was around 83%, and the demand also is greater than the available supply of donor material. Apparently high graft survival rates often belie the fact that transplantation is often only available for individuals with a highly favorable clinical case. Those patients who are unfortunately regarded as being poorer candidates for transplant will rarely ever become recipients of much needed donor tissue.
There is a need to improve control of the immune response to promote host tolerance to allografted tissue such that host acceptance of transplanted material is increased. In addition, modulation of the immune response in the recipient so as to promote recognition of the foreign transplanted tissue as ‘self’ may also serve to reduce the dependency on lifelong immunosuppressive therapy. Further, improved immunomodulatory treatments may also effect the ability to match donor tissue with recipients in need of a transplant, by expanding the parameters for tissue type matching—i.e. by expanding the tolerance parameters for mismatch between the tissue type of the host and that of the donor. This is of primary importance for patients with rare tissue types, such as those from particular ethnic minorities.
The present invention seeks to overcome or at least reduce the problems that exist by providing compositions and methods for targeted modulation of the immune response and promoting proliferation and activity of Treg cells that will suppress the anti-donor response and/or the chronic vascular rejection process. Not only does the targeted mode of delivery bring immune-modulators to the site where they are needed, for example within the organ transplant, but also it reduces the overall exposure of the patient to bio-active components that may carry toxic side-effects at irrelevant sites.